Oxybutynin is useful for treating stress and urge urinary incontinence (over active bladder). DITROPAN™ tablets are commercially available tablets that provide a rapid release of oxybutynin in the stomach and upper intestinal tract. Rapid release tablets are typically administered at a rate of about 3-4 tablets per day to treat urinary incontinence. Rapid release tablets, however, typically have undesirable side effects associated with them due to the high plasma oxybutynin concentrations they provide. These tablets also have a short duration of action due to the short half-life (t1/2≈2 hr) of oxybutynin in plasma.
In order to overcome these disadvantages, controlled release tablets of oxybutynin have been developed. In general, known controlled release tablets provide a sustained delivery of oxybutynin for a period of up to 8-30 hours after administration depending upon the formulation used. Sequential administration (2-3 times per day) of oxybutynin tablets having the same release profile is known.
A number of publications disclose controlled release formulations containing oxybutynin: a) U.S. Pat. No. 5,788,987 to Busetti et al.; b) International Publication No. WO 00/19997 to Alza Corp.; c) International Publication No. WO 96/12477 to Leiras OY; and d) Japanese Patents No. 2,646,170 and No. 2,665,858 to Nippon Hoechst Marion Roussel Ltd. A number of scientific publications disclose extended and controlled release formulations containing oxybutynin. In addition, Alza Corporation currently markets DITROPAN XL™, which is a controlled release tablet formulation containing oxybutynin. None of these publications disclose a combination formulation or pharmaceutical composition containing oxybutynin and another drug.
U.S. Pat. No. 5,399,359 to Baichwal, the entire disclose of which is hereby incorporated by reference, discloses many different controlled release tablet formulations that provide a controlled release of oxybutynin for periods of up to 8, 12, 16, 18, 24 or 30 hours. This patent does not disclose the combined administration of oxybutynin and another drug used to treat incontinence.
U.S. Pat. No. 5,912,268, No. 5,840,754 and No. 5,674,895 to Guittard, the entire disclosures of which are hereby incorporated by reference, disclose osmotic device formulations that deliver oxybutynin at a controlled rate for a period of about 24 hours. This patent does not disclose the combined administration of oxybutynin and another drug used to treat incontinence.
Appell et al. (“Clinical Evaluation of a Sustained Release Form of Oxybutynin, Urodynamics Society Symposium Abstracts (1990), pg. 228), the entire disclosure of which is hereby incorporated by reference, discloses a controlled release tablet DITROPAN™ SR that provides a controlled delivery of oxybutynin for about 8-12 hours. This publication does not disclose the combined administration of oxybutynin and another drug used to treat incontinence.
Sirkiä et al. (“Use of hydrophilic polymers to control drug release from press-coated oxybutynin hydrochloride tablets”, S.T.P. Pharmacia Sci. (1993), 3(6), pg. 453-458), the entire disclosure of which is hereby incorporated by reference, discloses a controlled release tablet formulation that provides a controlled delivery of oxybutynin for about 8-12 hours. This publication does not disclose the combined administration of oxybutynin and another drug used to treat incontinence.
Japanese Patent Applications Serial No. 9,388 and No. 163,901 to Enomoto et al., the entire disclosures of which are hereby incorporated by reference, disclose controlled release tablet formulations that deliver oxybutynin at a controlled rate for a period of about 12 hours for once or twice-a-day administration. These patents do not disclose the combined administration of oxybutynin and another drug used to treat incontinence.
A number of scientific publications disclose the results of tests on the therapeutic, pharmacological and/or pharmacodynamic properties of formulations containing darifenacin ((S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2-diphenyl-acetamide). The darifenacin formulations described in these publication include only i.v., i.p., and immediate release formulations. None of these references, however, disclose the combined administration of darifenacin and oxybutynin.
International Publication No. WO 97/09980 and U.S. Pat. No. 6,106,864 to Dolan et al. of Pfizer, Inc. discloses a controlled release formulation comprising darifenacin, wherein at least 10% of the darifenacin is delivered to the lower gastrointestinal tract. Dolan et al. disclose that the controlled release formulation can be any of a number of different formulations, including osmotic devices, as long as it provides the specified release profile. Dolan et al., however, do not disclose or suggest the coadministration of oxybutynin with darifenacin.
Dmochowski et al. (Urology (2000), 56(6), Suppl. A, pp. 41-49) disclose a number of different therapeutic agents for the treatment of incontinence. Dmochowski et al., however, do not disclose or suggest the coadministration of oxybutynin with darifenacin.
International Publication No. WO 97/18814 to Pfizer Research and Development Company discloses a number of controlled release formulations. One example in the disclosure includes a controlled release tablet comprising darifenacin. This publication also does not disclose or suggest the coadministration of oxybutynin with darifenacin.
A number of scientific publications disclose the results of clinical tests comparing the therapeutic, pharmacological, and/or pharmacodynamic properties of formulations containing tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine). The formulations include controlled, immediate or rapid release formulations. None of these references, however, disclose the combined administration of tolterodine and oxybutynin.
International Publication No. WO 00/12069 to Pharmacia Upjohn AB discloses controlled release formulations containing tolterodine. This publication, however, does not disclose a combination formulation containing tolterodine and oxybutynin. In addition, Pharmacia Upjohn currently markets DETROL LA™, which is an extended release capsule formulation containing tolterodine.
Side effects in drug therapies for the treatment of incontinence continue to be a problem. Practitioners are in search of therapies having an improved toxicity profile, enhanced therapeutic efficacy or reduced total drug dose requirement.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770 and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference.
Osmotic devices have demonstrated utility in delivering beneficial active agents, such as medicines, nutrients, food, pesticides, herbicides, germicides, algaecides, chemical reagents, and others, to an environment of use in a controlled manner over prolonged periods of time. Known devices include tablets, pills, and capsules.
Advancements in the art have focused on developing osmotic devices with improved semipermeable or porous membranes, various coatings surrounding the core and/or the semipermeable membrane, layered osmotically effective agents in the core of the device, specific release profiles for specific active substances, and specific membrane or core compositions.
U.S. Pat. Nos. 4,931,285, 5,006,346 and 5,160,743 to Edgren et al., U.S. Pat. Nos. 5,160,744, 5,190,765 and No. 5,252,338 to Jao et al., U.S. Pat. Nos. 4,612,008, 4,765,989 and No. 5,082,668 to Wong et al., U.S. Pat. No. 4,327,725 to Cortese et al., U.S. Pat. No. 5,208,037 to Wright et al., U.S. Pat. No. 4,904,474 to Theeuwes et al. and U.S. Pat. No. 4,627,971 to Ayer disclose osmotic devices comprising a bi-layered core surrounded by a semipermeable membrane having at least one hole (or passageway). The bi-layered core, however, comprises a first push-layer containing no drug and a second layer containing drug. The hole(s) can be placed anywhere along the semipermeable membrane. These patents do not disclose a core having two different drug-containing layers, each providing a controlled release of drug through a respective hole in the semipermeable membrane.
U.S. Pat. No. 5,543,155 to Fekete et al. discloses an osmotic device comprising a bi-layered core surrounded by a semipermeable membrane having two holes (or passageways). The bi-layered core, however, comprises a first push-layer containing no drug and a second layer containing drug. The hole(s) can be placed anywhere along the semipermeable membrane. This patent does not disclose a core having two different drug-containing layers, each providing a controlled release of drug through a respective hole in the semipermeable membrane.
U.S. Pat. No. 4,662,880 to Hamel et al., U.S. Pat. Nos. 4,723,957, 4,867,969 and 4,971,790 to Magruder et al. disclose osmotic devices comprising a single-layered core surrounded by a semipermeable membrane having two oppositely placed holes. A drug-containing coat further surrounds the semipermeable membrane. These patents do not disclose a core having two different drug-containing layers, each providing a controlled release of drug through a respective hole in the semipermeable membrane.
U.S. Pat. No. 4,624,847 to Ayer et al. discloses an osmotic device comprising a semipermeable membrane surrounding a compartment that houses a drug-containing polymer that increases in size and releases drug. The semipermeable membrane has two oppositely placed holes for releasing drug. These patents do not disclose a core having two different drug-containing layers, each providing a controlled release of drug through a respective hole in the semipermeable membrane.
U.S. Pat. No. 4,915,954 to Ayer et al. and U.S. Pat. No. 4,814,181 to Jordan et al. disclose an osmotic device having a bi-layered core surrounded by a semipermeable membrane. The first layer comprises a first drug that is released from the core rapidly over a period of 2 min to 2 hr. The second layer comprises a second drug that is released from the core at a controlled rate over a long period of time. The layers of the core are in intimate contact and are not separated by another layer, lamina or membrane. The semipermeable membrane can have two holes, one hole adjacent each of the two layers of the core such that each layer releases drug through its own respective hole. The Ayer et al. and Jordan et al. patents do not disclose an osmotic device having a bi-layered core, wherein the layers are in contact with each other and in laminar arrangement with respect to one another and wherein each layer provides a prolonged and controlled release of an active agent.
U.S. Pat. No. 4,455,143 to Theeuwes et al. discloses an osmotic device having two compartments defined by a surrounding semipermeable membrane and a partition between the compartments. The semipermeable membrane has two oppositely placed holes, one for each compartment. Each compartment contains a drug that is delivered at a controlled rate through a respective hole in the surrounding membrane. The partition is require and retains its integrity during operation of the osmotic device.
U.S. Pat. No. 5,866,164 to Kuczynski et al. of Alza Corporation discloses an osmotic device having a bi-layered core surrounded by a semipermeable membrane. There is no partition between the layers. The core includes a drug-containing layer and a push-layer; and passageways in the surrounding semipermeable membrane only communicate the drug-containing layer, and not the push-layer, to the exterior of the device. This osmotic device was specifically designed to release only the drug in the drug-containing layer and retain the drug in the push-layer.
While the prior art discloses a wide variety of osmotic devices, none of the prior art discloses an osmotic device that provides a controlled delivery of at least two different active agents, wherein: a) the core of the osmotic device is bi-layered and comprises a first pharmaceutical composition in laminar arrangement with a second pharmaceutical composition; b) the pharmaceutical compositions are in contact with one another; and c) drug is released from each layer through a passageway in a surrounding membrane (coat).
None of the prior art discloses a method of treating incontinence by coadministering oxybutynin with another drug, such as darifenacin or tolterodine. Likewise, none of the references disclose a pharmaceutical composition, or dosage form, comprising a combination of darifenacin and oxybutynin or of tolterodine and oxybutynin.
None of the prior art discloses an osmotic device comprising a dual layered core, wherein each layer of the core provides a controlled release of its respective drug and wherein the layers are in intimate contact, i.e., the layers are not separated by a partition, and wherein neither layer is required to be a push-layer, per se.